Early exposure of pregnant women to non‐steroidal anti‐inflammatory drugs delivered outside hospitals and preterm birth risk: nationwide cohort study

OBJECTIVE To assess the risk of preterm birth associated with nonsteroidal anti-inflammatory drugs (NSAIDs), focusing on early exposure in the period from conception to 22 weeks of gestation (WG). DESIGN National population-based retrospective cohort study SETTING: The French National Health Insurance Database that includes hospital discharge data and health claims data. POPULATION Singleton pregnancies (2012-2014) with a live birth occurring after 22WG from women between 15 and 45 years old and insured the year before the first day of gestation and during pregnancy were included. We excluded pregnancies for which anti-inflammatory medications was dispensed after 22WG. METHODS The association between exposure and risk of preterm birth was evaluated with GEE models, adjusting on a large number of covariables, socio-demographic variables, maternal comorbidities, prescription drugs, and pregnancy complications. MAIN OUTCOME MEASURES Prematurity, defined as a birth that occurred before 37WG. RESULTS Among our 1,598,330 singleton pregnancies, early exposure to non-selective NSAIDs was associated with a significantly increased risk of preterm birth, regardless of the severity of prematurity: aOR=1.76[1.54-2.00] for extreme prematurity (22-27WG), 1.28[1.17-1.40] for moderate prematurity (28-31WG) and 1.08[1.05-1.11] for late prematurity (32-36WG), with non-overlapping confidence intervals. We identified 5 NSAIDs for which the risk of premature birth was significantly increased: ketoprofen, flurbiprofen, nabumetone, etodolac, and indomethacin (for the latter, aOR=1.92[1.37-2.70] with aOR=9.33[3.75-23.22] for extreme prematurity). CONCLUSION Overall, non-selective NSAID use (delivered outside hospitals) during the first 22WG was found to be associated with an increased risk of prematurity. However, the association differs among NSAIDs.